Individualized screening for chaperone activity in Gaucher disease using multiple patient derived primary cell lines

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Chaperone therapy aims to restore protein function using small molecules.
• Ambroxol is a potential chaperone for Gaucher disease (GD), caused by GBA gene mutations leading to glucocerebrosidase (GCase) deficiency.

Purpose of the Study:

• To evaluate the mutation-dependent chaperone activity of ambroxol in Gaucher disease.
• To identify optimal cell models for screening ambroxol efficacy in GD patients.

Main Methods:

• Compared ambroxol's effect on GCase activity in primary cells from GD patients with diverse GBA genotypes.
• Assessed cell models including PBMCs, macrophages, and urine-derived kidney epithelial cells.

Main Results:

• Ambroxol enhanced GCase activity in wild-type and N370S heterozygous cells but was ineffective in complex GBA alleles.
• Response varied in neuropathic GD patients with L444P/L444P genotype.
• PBMCs, macrophages, and kidney cells showed potential for drug screening.

Conclusions:

• Gaucher disease chaperone therapy efficacy is influenced by multiple factors beyond GBA genotype.
• Personalized screening is essential for evaluating ambroxol efficacy, particularly for neuronopathic GD.
• Non-invasive cell models like kidney cells offer promise for pediatric GD drug screening.